Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial. METHODS: Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate. RESULTS: The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up. CONCLUSIONS: Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.

Multicenter analysis of CIREN occupant lumbar bone mineral density and correlation with age and fracture incidence.

OBJECTIVE: This study aimed to quantify lumbar volumetric bone mineral density (vBMD) for 873 seriously injured Crash Injury Research and Engineering Network (CIREN) motor vehicle crash occupants (372 male, 501 female) from 8 centers using phantomless computed tomography scans and to associate vBMD with age, fracture incidence, and osteopenia/osteoporosis diagnoses. The novelty of this work is that it associates vBMD with region of injury by applying an established method for vBMD measurement using phantomless computed tomography (CT). METHODS: A validated phantomless CT calibration method that uses patient-specific fat and muscle measurements to calibrate vBMD measured from the L1-L5 trabeculae was applied on 873 occupants from various CIREN centers. CT-measured lumbar vBMD < 145 mg/cc is indicative of osteopenia using a published threshold. CIREN occupant lumbar vBMD in milligrams per cubic centimeter was regressed against age, osteopenia/osteoporosis comorbidities, height, weight, body mass index (BMI), and the incidence of fracture in vertebral (cervical, thoracic, lumbar) and rib/sternum regions. RESULTS: Among the 873 occupants analyzed, 11% (92 occupants) were diagnosed as osteopenic in CIREN. Of these 92 occupants, 42% (39 occupants) had normal vBMD measures (≥145 mg/cc), suggesting possible misclassification in CIREN. Of the 134 occupants classified as osteopenic in vBMD analysis, 60% were not classified as osteopenic in CIREN, suggesting undiagnosed osteopenia, and 40% were correctly classified in CIREN. Age was negatively correlated with vBMD (P <.0001) and occupants with <145 mg/cc vBMD sustained a median number of 2 rib/sternum fractures compared to a median value of 0 rib/sternum fractures for the ≥145 mg/cc vBMD group (P <.0001). Vertebral fracture analysis revealed that the thoracolumbar region was the most common region of injury in the spine. Though the incidence of fracture was not significantly different in the thoracic (10% versus 6%, P =.122) and lumbar (16% versus 13%, P =.227) regions between the 2 bone quality groups, the proportion of thoracolumbar fractures was significantly higher in occupants with <145 mg/cc vBMD versus occupants with ≥145 mg/cc vBMD (24% versus 17%, P =.043). CONCLUSIONS: Low lumbar vertebral bone quality is associated with an increased number of rib/sternum fractures and a greater incidence of thoracolumbar vertebral body fractures within the CIREN population analyzed.

Lumbar Bone Mineral Density Phantomless Computed Tomography Measurements and Correlation with Age and Fracture Incidence.

OBJECTIVE: Low bone quality is a contributing factor to motor vehicle crash (MVC) injury. Quantification of occupant bone mineral density (BMD) is important from an injury causation standpoint. The first aim of this study was to validate a technique for measuring lumbar volumetric BMD (vBMD) from phantomless computed tomography (CT) scans. The second aim was to apply the validated phantomless technique to quantify lumbar vBMD in Crash Injury Research and Engineering Network (CIREN) occupants for correlation with age, fracture incidence, and osteopenia/osteoporosis diagnoses. METHODS: Quantitative CT (qCT) and dual-energy X-ray absorptiometry (DXA) were collected prospectively for 50 subjects and used to validate a technique to measure vBMD from 281 phantomless CT scans of CIREN occupants. Hounsfield unit (HU) measurements were collected from the L1-L5 vertebrae, right psoas major muscle, and anterior subcutaneous fat for all subjects and from 3 phantom ports with known mg/cc calcium hydroxyapatite values for the validation group. qCT calibration was accomplished using regressions between the phantom HU and mg/cc values to convert L1-L5 HU values to mg/cc. A phantomless calibration technique was developed where the fat and muscle HU values were linearly regressed against fat (-69 mg/cc) and muscle (77 mg/cc) to establish a conversion for L1-L5 HU measurements to mg/cc. vBMD calculated from qCT versus the phantomless method was compared for the 50 subjects to assess agreement and a mg/cc osteopenia threshold was established using DXA T-scores. CIREN HU measurements were converted to mg/cc using the phantomless technique and the mg/cc osteopenia threshold was used to compare vBMD to age, fracture incidence, and osteopenia comorbidity classifications in CIREN. RESULTS: Linear regression of lumbar vBMD derived from the qCT versus phantomless calibrations showed excellent agreement (R(2) = 0.87, P <.0001). A 145 mg/cc threshold for osteopenia was established (sensitivity = 1, specificity = 0.57) and 44 CIREN occupants had vBMD below this threshold. Of these 44 occupants, 64% were not classified as osteopenic in CIREN, but vBMD suggested undiagnosed osteopenia. Age was negatively correlated with vBMD in both sexes (P <.0001) and CIREN occupants with less than 145 mg/cc vBMD sustained an average 1.7 additional rib/sternum fractures (P =.036). CONCLUSIONS: Because lumbar vBMD was estimated from phantomless CT scans with accuracy similar to qCT, the phantomless technique can be broadly applied to both prospectively and retrospectively assess patient bone quality for research and clinical studies related to MVCs, falls, and aging.

Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study.

CONTEXT: Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification. OBJECTIVE: Our objective was to assess the relationships between sclerostin, BMD, and CP. DESIGN: Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP. PARTICIPANTS: A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years. MAIN OUTCOME MEASURES: Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured. RESULTS: Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm3, lumbar vBMD was 180.7/47.0/179.0 mg/cm3, coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0, and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women (P<.0001). Before and after adjusting for age, sex, body mass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbar vertebrae vBMD (P<.0001). Sex-stratified analyses verified significant relationships in both men and women (both P<.001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P=.03). CONCLUSIONS: In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP.

Plasma Dickkopf1 (DKK1) concentrations negatively associate with atherosclerotic calcified plaque in African-Americans with type 2 diabetes.

BACKGROUND: Bone mineral density (BMD) and atherosclerotic arterial calcified plaque (CP) demonstrate inverse relationships through unknown mechanisms. Dickkopf-1 (DKK1) is an endogenous inhibitor of bone formation, and serum DKK1 has been associated with impaired osteoblast activation and susceptibility to bone loss. Plasma DKK1, BMD in the spine, and CP in three arterial beds were assessed in African-Americans (AAs) to determine relationships of serum DKK1 with atherosclerotic vascular calcification. METHODS: Plasma DKK1, computed tomography-derived trabecular volumetric BMD (vBMD) in thoracic and lumbar vertebrae, and coronary artery, carotid artery, and aortoiliac CP were measured in 450 unrelated AAs with type 2 diabetes. Generalized linear models were fitted to test for associations between DKK1, vBMD, and CP. RESULTS: Participants were 56% female with mean/SD/median age of 55.4/9.5/55.0 yr, diabetes duration of 10.3/8.2/8.0 yr, plasma DKK1 of 481.6/271.8/417 pg/ml, coronary artery CP mass score of 284/648/13, carotid artery CP mass score of 46/132/0, and aortoiliac CP mass score of 1613/2910/282. Adjusting for age, sex, body mass index, mean arterial blood pressure, smoking, hemoglobin A(1c), and low-density lipoprotein-cholesterol, DKK1 was inversely associated with coronary artery and aortoiliac CP [parameter estimates -0.0011 (P = 0.0137) and -0.0010 (P = 0.0214), respectively], with a trend for carotid artery CP (P = 0.1404). No associations were observed between DKK1 and vBMD in the thoracic or lumbar vertebrae. CONCLUSIONS: Plasma DKK1 levels were inversely associated with coronary artery and aortoiliac CP, but not vBMD, in this cross-sectional study of AAs with type 2 diabetes. DKK1 may play a role in vascular mineral metabolism in this clinical setting.

Relationships between serum adiponectin and bone density, adiposity and calcified atherosclerotic plaque in the African American-Diabetes Heart Study.

CONTEXT: Adiposity, bone mineral density (BMD), and calcified atherosclerotic plaque (CP) exhibit complex interrelationships that are not well understood. Adipokines vary in relation to changes in body composition and may play roles in regulation of BMD and risk of cardiovascular disease. OBJECTIVE: Our objective was to examine the relationship between serum adiponectin and quantitative computed tomography-derived measures of volumetric BMD (vBMD) in thoracic and lumbar vertebrae, adipose tissue volumes, and CP in coronary, carotid, and infrarenal aortoiliac arteries. Generalized linear models were fitted to test for associations between adiponectin and measured phenotypes. PARTICIPANTS: A total of 479 unrelated African Americans with type 2 diabetes, 57% female with a mean ± SD (median) age of 55.6 ± 9.5 (55.0) years and diabetes duration of 10.3 ± 8.2 (8.0) years. RESULTS: Serum adiponectin was 8.26 ± 7.41 (6.10) µg/mL, coronary artery CP mass score was 280 ± 634 (14), carotid artery CP was 47 ± 133 (0), and aortoiliac CP was 1616 ± 2864 (319). Women had significantly higher body mass index and serum adiponectin and lower coronary and carotid artery calcium than males (all P < .05). Before and after adjusting for age, sex, body mass index, mean arterial pressure, smoking status, hemoglobin A1c, thiazolidinedione use, and low-density lipoprotein-cholesterol, adiponectin was inversely associated with thoracic and lumbar vertebral vBMD [parameter estimates (PEs) of -0.06 and -0.021, respectively; both P < .0005], visceral adipose tissue (PE -0.02; P < 0.0001), and C-reactive protein (PE -0.07; P < .0001) and positively associated with intermuscular adipose tissue (PE 0.01; P = .03). After covariate adjustment, significant associations were not observed between adiponectin and CP in any vascular bed (P > .1). CONCLUSION: Serum adiponectin levels were inversely associated with cross-sectional measures of thoracic and lumbar vertebral vBMD, inflammation, and visceral adiposity in African Americans but not with vascular CP after adjustment for covariates. The data support a regulatory/signaling role for adiponectin in the modulation of bone density.

Admixture mapping of coronary artery calcified plaque in African Americans with type 2 diabetes mellitus.

BACKGROUND: The presence and severity of coronary artery calcified plaque (CAC) differs markedly between individuals of African and European descent, suggesting that admixture mapping may be informative for identifying genetic variants associated with subclinical cardiovascular disease. METHODS AND RESULTS: Admixture mapping of CAC was performed in 1040 unrelated African Americans with type 2 diabetes mellitus from the African American-Diabetes Heart Study, Multi-Ethnic Study of Atherosclerosis and Family Heart Study using the Illumina custom ancestry informative marker panel. All cohorts obtained computed tomography scanning of the coronary arteries using identical protocols. For each ancestry informative marker, the probability of inheriting 0, 1, and 2 copies of a European-derived allele was determined. Linkage analysis was performed by testing for association between each ancestry informative marker using these probabilities and CAC, accounting for global ancestry, age, sex, and study. Markers on 1p32.3 in the GLIS1 gene (rs6663966, logarithm of odds [LOD]=3.7), 1q32.1 near CHIT1 (rs7530895, LOD=3.1), 4q21.2 near PRKG2 (rs1212373, LOD=3.0), and 11q25 in the OPCML gene (rs6590705, LOD=3.4) had statistically significant LOD scores, whereas markers on 8q22.2 (rs6994682, LOD=2.7), 9p21.2 (rs439314, LOD=2.7), and 13p32.1 (rs7492028, LOD=2.8) manifested suggestive evidence of linkage. These regions were uniformly characterized by higher levels of European ancestry associating with higher levels or odds of CAC. Findings were replicated in 1350 African Americans without diabetes mellitus and 2497 diabetic European Americans from Multi-Ethnic Study of Atherosclerosis and the Diabetes Heart Study. CONCLUSIONS: Fine mapping these regions will likely identify novel genetic variants that contribute to CAC and clarify racial differences in susceptibility to subclinical cardiovascular disease.

Relationships between calcified atherosclerotic plaque and bone mineral density in African Americans with type 2 diabetes.

Inverse relationships have been reported between bone mineral density (BMD) and calcified atherosclerotic plaque (CP). This suggests these processes may be related. We examined relationships between BMD and CP in 753 African Americans with type 2 diabetes from 664 families, accounting for the effects of modifiable cardiovascular disease (CVD) risk factors. Association analyses were performed using generalized estimating equations (GEEs) to assess cross-sectional relationships between computed tomography-determined measures of thoracic and lumbar vertebral volumetric BMD (vBMD) and CP in the coronary and carotid arteries and infrarenal aorta. Significant inverse associations were seen between thoracic and lumbar vBMD and CP in all three vascular beds in unadjusted analyses. A fully adjusted model accounting for age, sex, body mass index, systolic blood pressure, low-density lipoprotein cholesterol, C-reactive protein, hemoglobin A(1c), smoking, and hormone-replacement therapy revealed significant inverse associations between thoracic vBMD and CP in coronary and carotid arteries and aorta, whereas lumbar vBMD was associated with CP in coronary artery and aorta. Inverse associations exist between vertebral BMD and calcified atherosclerotic plaque in African-American men and women with type 2 diabetes. This relationship was independent of conventional CVD risk factors and supports the hypothesis that bone metabolism and atherosclerotic plaque mineralization are related processes.

Ethnic differences in the relationship between pericardial adipose tissue and coronary artery calcified plaque: African-American-diabetes heart study.

BACKGROUND: Calcified atherosclerotic plaque (CP) is less prevalent and less severe in African-Americans (AA), relative to European Americans (EA). Because pericardial adipose tissue (PAT) is associated with CP in the neighboring coronary arteries, we explored ethnic-specific relationships between PAT and CP. METHODS: PAT volume and coronary and aortic CP were measured in 561 EA and 575 AA subjects with type 2 diabetes using single and multidetector computed tomography. Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for associations between PAT and CP. RESULTS: Mean (sd) ages of AA and EA participants were 56.7 (9.5) and 62.0 (8.9) yr, respectively; diabetes duration was 10.5 (8.1) and 10.1 (7.3) yr; and PAT volume was 86.9 (38.6) and 131.7 (55.3) cm3/45 mm. In AA and EA participants, respectively, mean (sd) coronary CP mass scores were 803 (1,889) and 1,465 (2,847) mg calcium; and aortic CP, 5,407 (10,651) and 10,090 (15,087) mg calcium. Adjusting for age, gender, body mass index, blood pressure, height, smoking, lipid-lowering medications, C-reactive protein, albuminuria, high-density lipoprotein-cholesterol, and triglycerides, parameter estimates for the relationship between PAT and log(coronary CP+1) were 0.012 in AA (P<0.0001) and 0.003 (P=0.24) in EA, with a significant ethnic difference (P=0.019). No significant relationships or ethnic differences were observed between PAT and aortic CP (P=0.24, fully adjusted model). CONCLUSIONS: Pericardial adiposity is strongly associated with coronary atherosclerosis in AA with type 2 diabetes. Novel cardiovascular disease risk factors such as PAT may contribute to ethnic disparities in susceptibility to development of coronary atherosclerosis.

Ethnic differences in the relationship between albuminuria and calcified atherosclerotic plaque: the African American-diabetes heart study.

OBJECTIVE: Despite higher rates of nephropathy, calcified atherosclerotic plaque is less prevalent in African Americans with diabetes relative to European Americans. We explored ethnicity-specific relationships between albuminuria and calcified plaque involving the infrarenal aorta, coronary artery, and carotid artery in 835 European American and 393 African American subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for association between the principal component of calcified plaque in the three vascular beds and urine albumin-to-creatinine ratio (ACR). RESULTS: Mean +/- SD ages of African American and European American participants were 56.7 +/- 9.6 and 61.7 +/- 9.1 years, respectively, with diabetes duration of 10.4 +/- 7.4 and 10.0 +/- 7.3 years and median urine ACR of 17.5 and 13.4 mg/g. In African American and European American participants, respectively, median calcified plaque mass scores were 53.5 and 291 for coronary artery, 3 and 35.5 for carotid artery, and 761 and 3,237 for aorta. With adjustment for age, sex, glomerular filtration rate, and BMI, albuminuria was significantly associated with calcified plaque in European Americans (P = 3.4 x 10(-8)) but not in African Americans (P = 0.33), with significant ethnic interaction (P = 0.01). Ethnic differences in this relationship persisted after adjustment for blood pressure, smoking, lipids, and use of ACE inhibitors or angiotensin receptor blockers. CONCLUSIONS: Albuminuria is strongly associated with severity of calcified plaque in European Americans with diabetes but not in African Americans. Disparities in this relationship may contribute to ethnic differences in the rates of cardiovascular disease that are observed in subjects with type 2 diabetes.

Regional adipose tissue associations with calcified atherosclerotic plaque: African American-diabetes heart study.

Coronary artery calcified atherosclerotic plaque (CP) is strongly associated with nonsubcutaneous adipose tissue, particularly pericardial adipose tissue (PAT), in community-based studies. We tested for relationships between regional adipose tissue depots and CP in African Americans with longstanding type 2 diabetes. Infrarenal aorta, coronary, and carotid artery CP and pericardial, visceral, intermuscular, and subcutaneous organ-specific adipose tissue volumes were measured using single and multidetector computed tomography (CT) in 422 African Americans with type 2 diabetes. Generalized estimating equations using exchangeable correlation and the sandwich estimator of the variance were used to test for associations between CP and adipose tissue depots. Mean (s.d.) age was 56.5 (7.6) years, diabetes duration 10.3 (7.6) years, PAT 85.3 (36.1) cm(3)/45 mm and visceral adipose tissue (VAT) 174.9 (70.1) cm(3)/15 mm. Adjusting for age, gender, BMI, blood pressure, medications, proteinuria, smoking, lipids, and 25-hydroxyvitamin D, PAT was positively associated with the presence (P = 0.009) and quantity of coronary artery CP in African Americans (P = 0.004), as well as the quantity of infrarenal aorta CP (P = 0.004). As in European Americans, PAT is associated with CP in African Americans with type 2 diabetes. Ethnic differences in the relationships between organ-specific adipose tissue depots and atherosclerosis require further study.

Vitamin d, adiposity, and calcified atherosclerotic plaque in african-americans.

CONTEXT: Inverse associations are reported between circulating 25-hydroxyvitamin D and visceral adiposity. The effects of vitamin D levels on atherosclerosis are unknown. OBJECTIVE: The objective of this study was to test for relationships between vitamin D, adiposity, bone density, and atherosclerosis in African-Americans. DESIGN: Circulating 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact PTH, C-reactive protein and computed tomography-derived calcified atherosclerotic plaque (CP), bone density, and fat volumes were measured. SETTING: Examinations were performed at a single outpatient general clinical research center visit. SUBJECTS: Three hundred forty African-Americans with type 2 diabetes were evaluated. Mean +/- SD age was 55.6 +/- 9.6 yr, diabetes duration 10.6 +/- 8.3 yr, glomerular filtration rate 1.6 +/- 0.5 ml/sec, body mass index 35.6 +/- 8.7 kg/m(2), and 25-hydroxyvitamin D concentration 50.4 +/- 30.5 nmol/liter. MAIN OUTCOME MEASURE: Biomarkers were tested for association with pericardial, visceral, im, and sc adipose tissues; thoracic and lumbar vertebral bone density; and aorta, coronary, and carotid artery CP. RESULTS: Adjusting for age, gender, body mass index, glycosylated hemoglobin, and glomerular filtration rate, 25-hydroxyvitamin D was negatively associated with visceral adiposity (P = 0.009) and positively associated with carotid artery CP and aorta CP (P = 0.013 and 0.014, respectively) but not with coronary artery CP or bone density. CONCLUSIONS: We confirmed an inverse association between vitamin D and visceral adiposity in African-Americans with diabetes. In addition, positive associations exist between 25-hydroxyvitamin D and aorta and carotid artery CP in African-Americans. The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African-Americans are unknown. Prospective trials are needed to determine the cardiovascular effects of supplemental vitamin D in this ethnic group.